Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.
Nat Genet
; 54(9): 1305-1319, 2022 09.
Article
in En
| MEDLINE
| ID: mdl-35982159
ABSTRACT
To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autistic Disorder
/
Autism Spectrum Disorder
Type of study:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2022
Document type:
Article
Affiliation country:
United States